Peripheral neuropathy (PN) is one of the more common clinical diseases, presenting as a separate entity or a frequent symptom of a wide spectrum of diseases. However, investigation into the pathophysiology of PN is difficult through traditional investigative methods. Thus, the inherited neuropathies provide a useful approach to investigate the important components that lead to the development of PN. Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and one of the most common of all inherited disorders. The positional cloning approach has been highly successful in the elucidation of the genetic defects in CMT, particularly type l, the demyelinating form of the disease. This proposal is a continuation of our work using these techniques towards elucidating the defect leading to the axonal CMT form of the disease, CMT type 2A (CMT2) - CMT 2 is more variable in its presentation than type l and its electromyographical changes more closely mimic those seen in the common, idiopathic axonal neuropathies. We have previously demonstrated linkage-of one form of CMT2, CMT2A, to a small region of chromosome 1p36. Subsequent work in our laboratory has mapped additional markers in the region, establishing initial YAC contigs from the flanking markers and narrowIng the flanking region to approximately 1 megabase. We propose to complete this contig, develop additional markers and narrow the flanking region further using haplotype analysis. Once reduced further, direct selection will be the primary method used to develop new candidate genes in the region and eventually locate candidate coding regions to identify the defect in CMT2A. Insight into the pathways and defects leading to these disorders will not only provide information towards the pathophysiology of neuropathy, but to genes that are important to normal axonal function and physiology as well.